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DE10141650C1 - Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate - Google Patents

Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate

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Publication number
DE10141650C1
DE10141650C1 DE10141650A DE10141650A DE10141650C1 DE 10141650 C1 DE10141650 C1 DE 10141650C1 DE 10141650 A DE10141650 A DE 10141650A DE 10141650 A DE10141650 A DE 10141650A DE 10141650 C1 DE10141650 C1 DE 10141650C1
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Prior art keywords
fentanyl
active ingredient
tts
weight
polyacrylate
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DE10141650A
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German (de)
Inventor
Walter Mueller
Thomas Hille
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LTS Lohmann Therapie Systeme AG
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LTS Lohmann Therapie Systeme AG
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Application filed by LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Priority to DE10141650A priority Critical patent/DE10141650C1/en
Priority to DE50209364T priority patent/DE50209364D1/en
Priority to DE20221161U priority patent/DE20221161U1/en
Priority to KR1020047002655A priority patent/KR100895189B1/en
Priority to ES02762336T priority patent/ES2280563T3/en
Priority to PCT/EP2002/007664 priority patent/WO2003018075A2/en
Priority to CNA028164261A priority patent/CN1713899A/en
Priority to AU2002328328A priority patent/AU2002328328B2/en
Priority to MXPA04001676A priority patent/MXPA04001676A/en
Priority to CN2011101937323A priority patent/CN102258501A/en
Priority to DE20221160U priority patent/DE20221160U1/en
Priority to BR0212026-7A priority patent/BR0212026A/en
Priority to DE20221087U priority patent/DE20221087U1/en
Priority to PT02762336T priority patent/PT1418894E/en
Priority to JP2003522590A priority patent/JP5405709B2/en
Priority to EP02762336A priority patent/EP1418894B1/en
Priority to EP07001087A priority patent/EP1825849A1/en
Priority to CA2457401A priority patent/CA2457401C/en
Priority to US10/487,393 priority patent/US10568845B2/en
Priority to EP07001088A priority patent/EP1782799A3/en
Priority to DK02762336T priority patent/DK1418894T3/en
Priority to DE20221159U priority patent/DE20221159U1/en
Priority to AT02762336T priority patent/ATE352293T1/en
Publication of DE10141650C1 publication Critical patent/DE10141650C1/en
Application granted granted Critical
Priority to ZA200400314A priority patent/ZA200400314B/en
Priority to CY20071100407T priority patent/CY1106411T1/en
Priority to JP2010232409A priority patent/JP5639843B2/en
Priority to US16/263,743 priority patent/US10583093B2/en
Priority to US16/719,086 priority patent/US10940122B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a transdermal therapeutic system (TTS), comprising a backing layer, which is permeable to the active ingredient, at least one matrix layer, comprising fentanyl or an active agent analogous to fentanyl, based on polyacrylate and a protective layer to be removed before usage, characterised in that the polyacrylate polymer is self-adhesive, free of carboxyl groups, has a saturation solubility for fentanyl of 3 to 20 wt. %, preferably of 4 to 12 and particularly of 5 to 10 wt. % and the layers contain at least 80 % of the included active ingredient in a molecularly-dispersed, dissolved form.

Description

Fentanyl und fentanylanaloge Substanzen wie Sulfentanyl, Carfentanyl, Lofentanyl und Alfentanyl sind außerordentlich wirksame Analgetika. Das Erfordernis der nur geringen Dosierung und ihre physiko-chemischen Eigenschaften wie der n- Octanol-Wasser-Verteilungskoeffizient, Schmelzpunkt und das Molekulargewicht machen die transdermale Zufuhr dieser Substanzen in wirksamer Menge möglich und ihre pharmakokinetischen Eigenschaften wie die schnelle Metabolisierung und der relativ enge therapeutische Index die transdermale Zufuhr wünschenswert.Fentanyl and fentanylanaloge substances such as sulfentanyl, carfentanyl, lofentanyl and alfentanyl are extremely effective analgesics. The only requirement low dosage and their physico-chemical properties such as the n- Octanol / water partition coefficient, melting point and molecular weight make the transdermal supply of these substances possible in an effective amount and their pharmacokinetic properties such as rapid metabolism and the relatively narrow therapeutic index desirable transdermal delivery.

In der Tat ist seit einigen Jahren ein TTS mit Fentanyl als Wirkstoff auf dem Markt. Dieses System ist ein sogenanntes Reservoirsystem. Unter einem Reservoirsystem wird dabei ein System verstanden, das den Wirkstoff in einer flüssigen oder gelförmigen Zubereitung in einem aus einer undurchlässigen Folie, die als Rückschicht dient, und einer wirkstoffdurchlässigen Membran geformten Beutel enthält, wobei die Membran zusätzlich mit einer Kleberschicht zur Befestigung des Systems auf der Haut versehen ist. In diesem speziellen Fall ist Fentanyl in einem Gemisch aus Ethanol und Wasser gelöst. Weitere Einzelheiten dieses Systems können der US-Patentschrift 4,588,580 bzw. der DE-PS 35 26 339 entnommen werden, die beide eine detaillierte Beschreibung enthalten. In fact, a TTS with fentanyl as an active ingredient has been on the market for several years. This system is a so-called reservoir system. Under a reservoir system is understood as a system that contains the active ingredient in a liquid or gel-like preparation in an from an impermeable film, which as Backing serves, and a drug-permeable membrane shaped bag contains, the membrane additionally with an adhesive layer for fastening the System is provided on the skin. In this particular case, fentanyl is in one Mixture of ethanol and water dissolved. More details of this system can be found in US Pat. No. 4,588,580 and DE-PS 35 26 339 both contain a detailed description.  

Ein bandförmiges Präparat zur perkutanen Verabreichung enthaltend Fentanyl oder ein Salz von Fentanyl ist aus EP 842 662 A1 bekannt. Hier wird Natriumacetat als Zusatzstoff in die Kleberschicht des bandförmigen Präparats eingearbeitet, wodurch die hautirritierenden Eigenschaften des Präparats reduziert werden. Ebenso wird dadurch eine Erhöhung der Stabilität über einen längeren Zeitraum erzielt.A tape-like preparation for percutaneous administration containing fentanyl or a salt of fentanyl is known from EP 842 662 A1. Here is sodium acetate as Additive incorporated into the adhesive layer of the tape-like preparation, whereby the skin-irritating properties of the preparation are reduced. Likewise, thereby increasing stability over a longer period of time.

Reservoirsysteme haben allerdings den Nachteil, daß im Falle einer Undichtigkeit des Reservoirbeutels die wirkstoffhaltige Reservoirfüllung großflächig mit der Haut in Kontakt kommt und der Wirkstoff in zu hohen Dosen resorbiert wird. Dies ist speziell bei Fentanyl und seinen Derivaten sehr gefährlich, da eine Überdosierung sehr schnell zu Atemdepression und damit tödlichen Zwischenfällen führt. Mehrere solcher tödlichen bzw. fast tödlichen Zwischenfälle sind beschrieben in Clinical Pharmacokinet. 2000, 38(1), 59-89.However, reservoir systems have the disadvantage that in the event of a leak of the reservoir bag, the active substance-containing reservoir filling with the skin in Contact comes and the active ingredient is absorbed in too high doses. This is special very dangerous with fentanyl and its derivatives, since an overdose is very dangerous quickly leads to respiratory depression and thus fatal incidents. Several such fatal or almost fatal incidents are described in Clinical Pharmacokinet. 2000, 38 (1), 59-89.

Aufgabe dieser Erfindung war es nun ein transdermales therapeutisches System mit Fentanyl bzw. Fentanylanalogen bereitzustellen, das dem Benutzer eine erhöhte Sicherheit gegen eine versehentliche Aufnahme von Überdosen bietet.The object of this invention was now a transdermal therapeutic system with fentanyl or fentanyl analogs that provide the user with a offers increased security against accidental ingestion of overdoses.

Dies gelingt erfindungsgemäß dadurch, daß statt des Reservoirsystems ein Matrixsystem eingesetzt wird, bei dem der Wirkstoff direkt in ein selbstklebendes Polyacrylat eingearbeitet wird und damit selbst bei einer Beschädigung des Systems nicht in einer größeren als durch das TTS gegebenen Fläche mit der Haut in Kontakt kommen kann. Der Wirkstoff ist in einem solchen System im allgemeinen ganz, jedoch zu mindestens 80% in diesem Polymer molekulardispers gelöst, wobei die Sättigungslöslichkeit des Wirkstoffs im Polymer zwischen 3 und 20 Gewichtsprozenten liegt. Weiterhin hat es sich überraschenderweise gezeigt, daß bei der Verwendung von Polyacrylatklebern für die Herstellung von TTS mit Fentanyl und seinen Analogen nur Kleber ohne freie Carboxylgruppen geeignet sind.This is achieved according to the invention in that instead of the reservoir system Matrix system is used, in which the active ingredient directly in a self-adhesive Polyacrylate is incorporated and thus even if the Systems not in a larger area than that given by the TTS Skin can come into contact. The active substance is in such a system generally whole, but at least 80% in this polymer dissolved molecularly, the saturation solubility of the active ingredient in the polymer is between 3 and 20 percent by weight. Furthermore, it has Surprisingly shown that when using polyacrylate adhesives for the production of TTS with fentanyl and its analogs only glue without free Carboxyl groups are suitable.

Solche Matrixsysteme bestehen im einfachsten Fall aus einer Rückschicht, die für den Wirkstoff undurchlässig ist, einer selbstklebenden wirkstoffhaltigen Schicht und einer vor Gebrauch zu entfernenden Schutzschicht. In komplizierteren Ausführungen solcher Systeme schließt sich zusätzlich noch eine die Wirkstoff­ abgabe steuernde Membran an, die normalerweise noch mit einer Kleberschicht zur Befestigung des Systems auf der Haut versehen ist.In the simplest case, such matrix systems consist of a backing layer which is suitable for the active ingredient is impermeable, a self-adhesive active ingredient-containing layer and a protective layer to be removed before use. In more complicated ones Designs of such systems also include an active ingredient dispensing control membrane, usually with an adhesive layer to attach the system to the skin.

Die wirkstoffhaltigen Schichten eines solchen Matrixsystems gemäß dieser Erfindung bestehen aus Polyacrylaten. Da freie funktionelle Gruppen die Sättigungslöslichkeit von Fentanyl und seinen Derivaten in Polyacrylatklebern über den bevorzugten Bereich erhöhen, sind am besten solche Polyacrylatkleber geeignet, die über keine freien funktionellen Gruppen verfügen und lediglich aus Estern der Acryl- und/oder Methaycrylsäure und gegebenenfalls sonstigen Vinylverbindungen ohne freie funktionelle Gruppen wie Vinylacetat hergestellt werden. Allerdings können bei der Klebersynthese Monomere mit freien Hydroxylgruppen wie 2-Hydroxyethylacrylat oder 2-Hydroxyethylmethacrylat bis zu einem Anteil von 20 Gew.-% toleriert werden. Polyacrylate werden durch radikalische Polymerisation unter Verwendung von Acryl- und/oder Methacrylsäurederivaten hergestellt. Solche Derivate sind z. B. Ester. Beispielhaft für solche Derivate seien Acryl- und Methacrylsäurederivate genannt, insbesondere Ester von Alkoholen mit 1 bis 8 C-Atomen, die gegebenenfalls eine Hydroxylgruppe enthalten, wie 2-Ethylhexylacrylat, n-Octylacrylat, Propylacrylat, n- oder iso-Butylacrylat, 2-Hydroxyethylacrylat und Dimethylaminoethylacrylat bzw. die entsprechenden Methacrylate. Zusätzlich können auch andere polymerisierbare Vinylverbindungen ohne freie funktionelle Gruppen wie z. B. Vinylacetat mitverwendet werden, z. B. in Mengen von bis zu 50 Gew.-%. Die so hergestellten Polymere werden auch als statistische Copolymere bezeichnet, da allein die Mengenverteilung der eingesetzten Monomeren und der Zufall über die Zusammensetzung der Polymerketten entscheidet.The active substance-containing layers of such a matrix system according to this Invention consist of polyacrylates. Because free functional groups Saturation solubility of fentanyl and its derivatives in polyacrylate adhesives increase the preferred range, such polyacrylate adhesives are best suitable that have no free functional groups and only from Esters of acrylic and / or methacrylic acid and optionally others Vinyl compounds without free functional groups such as vinyl acetate become. However, monomers with free Hydroxyl groups such as 2-hydroxyethyl acrylate or 2-hydroxyethyl methacrylate up to  a proportion of 20 wt .-% are tolerated. Polyacrylates are made by radical polymerization using acrylic and / or Methacrylic acid derivatives produced. Such derivatives are e.g. B. esters. exemplary acrylic and methacrylic acid derivatives may be mentioned for such derivatives, in particular esters of alcohols with 1 to 8 carbon atoms, which may be a Contain hydroxyl group, such as 2-ethylhexyl acrylate, n-octyl acrylate, propyl acrylate, n- or iso-butyl acrylate, 2-hydroxyethyl acrylate and dimethylaminoethyl acrylate or the corresponding methacrylates. In addition, others can polymerizable vinyl compounds without free functional groups such as. B. Vinyl acetate can also be used, e.g. B. in amounts of up to 50 wt .-%. The so Polymers produced are also referred to as statistical copolymers because only the quantitative distribution of the monomers used and the chance of the The composition of the polymer chains is decisive.

Enthalten die Polymere freie Hydroxylgruppen, besteht die Möglichkeit, die Polymerketten zusätzlich durch mehrwertige Kationen wie Al3+ oder Ti4+ oder reaktive Substanzen wie Melamin zu vernetzen. Man macht von dieser Möglichkeit Gebrauch um das Molekulargewicht zu erhöhen und damit die Kohäsion der Polymere zu verbessern. Die Möglichkeit der Quervernetzung von Polyacrylaten, insbesondere von Polyacrylatklebern, ist besonders wertvoll, wenn die weichmachende Wirkung des in den Polymeren gelösten Wirkstoffs bzw. die weichmachende Wirkung von anderen Hilfsstoffen kompensiert werden muß. Der Kleber wird gewöhnlich in Form einer Lösung verwendet. Als Lösungsmittel dienen z. B. Ethylacetat, Hexan oder Heptan, Ethanol oder deren Mischungen. Diese werden während der Herstellung des TTS entfernt.If the polymers contain free hydroxyl groups, it is possible to additionally cross-link the polymer chains with polyvalent cations such as Al 3+ or Ti 4+ or reactive substances such as melamine. This option is used to increase the molecular weight and thus to improve the cohesion of the polymers. The possibility of crosslinking polyacrylates, especially polyacrylate adhesives, is particularly valuable if the softening effect of the active ingredient dissolved in the polymers or the softening effect of other auxiliaries has to be compensated for. The glue is usually used in the form of a solution. Z. B. ethyl acetate, hexane or heptane, ethanol or mixtures thereof. These are removed during the manufacture of the TTS.

In Tabelle 1 sind die Ergebnisse von Permeationsstudien gezeigt, die mit einem Kleber mit und einem Kleber ohne freie Carboxylgruppen (jedoch ohne Hydroxylgruppen) erreicht worden sind. In beide Kleber wurde der Wirkstoff in einer Konzentration von 5 Gewichtsprozenten eingearbeitet. Die Permeationsstudie wurde mittels dem Fachmann bekannter Franz-Diffusionszellen und Verwendung von menschlicher Haut durchgeführt. Table 1 shows the results of permeation studies with a Adhesive with and an adhesive without free carboxyl groups (however without Hydroxyl groups) have been reached. The active ingredient was used in both adhesives a concentration of 5 percent by weight. The Permeation study was carried out using Franz diffusion cells known to those skilled in the art and use of human skin.  

Tabelle 1 Table 1

Ergebnisse von Permeationsstudien mit Klebern mit und ohne freie Carboxylgruppen Results of permeation studies with adhesives with and without free carboxyl groups

Formul. 1: Polyacrylatkleber mit 4,8 Gew.-% freien Carboxylgruppen
Formul. 2: neutraler Polyarylatkleber ohne freie Carboxygruppen aber mit 5,2 Gew.-% freien HydroxylgruppenFormul. 1: polyacrylate adhesive with 4.8% by weight of free carboxyl groups
Formul. 2: neutral polyarylate adhesive without free carboxy groups but with 5.2% by weight free hydroxyl groups

Die Ergebnisse zeigen, daß ein neutraler Kleber ohne freie Carboxylgruppen einem carboxylgruppenhaltigen Kleber bezüglich der erreichbaren Permeationsraten deutlich überlegen ist.The results show that a neutral adhesive with no free carboxyl groups a carboxyl group-containing adhesive with regard to the achievable Permeation rates is clearly superior.

Eine wichtige Eigenschaft jedes wirkstoffhaltigen Polymers in der TTS- Technologie ist die Sättigungslöslichkeit des gewählten Polymers für den jeweiligen Wirkstoff. Dieser Parameter ist deshalb wichtig, weil die thermodynamische Aktivität des Wirkstoffs in der Matrix nicht von der absolut gelösten Menge des Wirkstoffs, sondern vielmehr vom Verhältnis der tatsächlichen Konzentration zu der Sättigungskonzentration abhängt. Da sich der Wirkstoff bei der Applikation des TTS auf die Haut in die Haut verteilen muß und sich dabei nicht Konzentrationen, sondern Aktivitäten angleichen, ist es zum Erreichen einer möglichst hohen Permeationsrate wichtig, die thermodynamische Aktivität des Wirkstoffs im TTS möglichst hoch zu wählen. Dies bedeutet, daß die Löslichkeit des Wirkstoffs in den wirkstoffhaltigen Teilen des TTS nicht zu hoch sein darf, da ansonsten die Wirkstoffkonzentration im TTS recht hoch sein muß um eine genügend hohe thermodynamische Aktivität zu erreichen. Dies ist unvorteilhaft, wenn der Wirkstoff in der hohen Konzentration die physikalischen Eigenschaften der wirkstoffhaltigen Teile des Systems nachteilig beeinflußt und/oder der Wirkstoff sehr teuer ist. Im Falle des Fentanyl treffen beide Gründe zu, wobei zusätzlich noch in Betracht zu ziehen ist, daß Fentanyl und seine Derivate zu den Betäubungsmitteln zählen und es allein schon deshalb wünschenswert ist, möglichst wenig Wirkstoff in das TTS einzuarbeiten bzw. die Wirkstoffausnutzung, d. h. das Verhältnis von während der Tragezeit des TTS abgegebenem Wirkstoff zum Gehalt des ungetragenen TTS möglichst groß zu gestalten.An important property of every active ingredient-containing polymer in TTS Technology is the saturation solubility of the chosen polymer for the respective active ingredient. This parameter is important because the thermodynamic activity of the active substance in the matrix is not absolutely absolute dissolved amount of the active ingredient, but rather on the ratio of actual concentration depends on the saturation concentration. Since the Distribute active ingredient when applying the TTS to the skin in the skin and it is not the concentration, but the activities that align Achieving the highest possible permeation rate important, the thermodynamic Select the activity of the active substance in the TTS as high as possible. This means that the Solubility of the active ingredient in the active ingredient-containing parts of the TTS not too high may be otherwise the active substance concentration in the TTS must be quite high  in order to achieve a sufficiently high thermodynamic activity. This is disadvantageous if the active ingredient in the high concentration the physical Properties of the drug-containing parts of the system adversely affected and / or the active ingredient is very expensive. In the case of fentanyl, both reasons apply to, and it should also be considered that fentanyl and its Derivatives are considered narcotics, and for that reason alone It is desirable to incorporate as little active ingredient as possible into the TTS Drug utilization, d. H. the ratio of while wearing the TTS delivered active ingredient to the content of unworn TTS as large as possible shape.

Unter dem Gesichtspunkt sollte die Sättigungslöslichkeit der wirkstoffhaltigen Schichten für ein Dreitage-TTS nicht unter 3 Gewichtsprozenten und nicht über 20 Gewichtsprozenten liegen. Bei höheren Sättigungslöslichkeiten wird selbst bei einer hohen spezifischen Permeationsrate die Wirkstoffausnutzung zu schlecht, und das TTS ist aus kommerziellen Gründen wegen des teuren Wirkstoffs nicht gut verkäuflich. Bevorzugt liegt aus diesen Gründen die Sättigungslöslichkeit zwischen 4 und 12 und besonders bevorzugt zwischen 5 und 10 Gewichtsprozenten.From the point of view, the saturation solubility of the active ingredient Layers for a three day TTS are not less than 3 percent by weight and not over 20 percent by weight. At higher saturation solubilities, even at a high specific permeation rate the drug utilization is too poor, and the TTS is not for commercial reasons because of the expensive active ingredient easy to sell. For these reasons, the saturation solubility is preferred between 4 and 12 and particularly preferably between 5 and 10 By weight.

Die Sättigungslöslichkeit von Fentanyl und seinen Analogen kann zusätzlich reduziert werden durch den Zusatz von Substanzen, die keine guten Löseeigenschaften für den Wirkstoff haben. Solche Substanzen sind z. B. flüssige Kohlenwassestoffe wie Dioctylcyclohexan, flüssiges Paraffin, Kohlenwasserstoffharze wie Polyterpene, insbesondere Polypinen oder polare Substanzen wie Glycerin, Di- und Triglycerin oder Polyethylenglykole, z. B. mit einem Molgewicht von 200 bis 1000. Diese Substanzen können mit dem Polyacrylatkleber eine homogene Mischung bilden oder aber als eine gesonderte Phase darin enthalten sein. Speziell Glycerin und seine Derivate liegen schon bei geringen Konzentrationen in der Matrix als gesonderte Phase, z. B. in Form von Tröpfchen vor. Durch die Zugabe solcher Substanzen kann insbesondere auch die höhere Sättigungslöslichkeit in Klebern mit freien Hydroxylgruppen kompensiert werden.The saturation solubility of fentanyl and its analogues can be additional are reduced by adding substances that are not good Have dissolving properties for the active ingredient. Such substances are e.g. B. liquid Hydrocarbons such as dioctylcyclohexane, liquid paraffin, Hydrocarbon resins such as polyterpenes, especially polypins or polar Substances such as glycerol, di- and triglycerol or polyethylene glycols, e.g. B. with a molecular weight of 200 to 1000. These substances can with the Polyacrylate adhesive form a homogeneous mixture or as a separate one Phase. Glycerin and its derivatives in particular are already included low concentrations in the matrix as a separate phase, e.g. B. in the form of Droplets before. By adding such substances, the compensated for higher saturation solubility in adhesives with free hydroxyl groups  become.

Tabelle 2 enthält einige Angaben zu den Sättigungslöslichkeiten von Fentanyl in einigen dieser Substanzen.Table 2 contains some information on the saturation solubility of fentanyl in some of these substances.

Tabelle 2 Table 2

Sättigungslöslichkeiten von Fentanyl in löslichkeitsvermindernden Zusätzen Saturation solubility of fentanyl in solubility-reducing additives

Der Einfluß von solchen Zusätzen läßt sich anhand von vergleichenden Permeationsstudien erkennen.The influence of such additives can be compared Recognize permeation studies.

In Tabelle 3 sind die Ergebnisse von Permeationsstudien mit Matrices auf Basis eines neutralen Polyacrylatkfebers mit freien Hydroxylgruppen mit und ohne solche Zusätze sowie eines Polyacrylatklebers ohne andere freie funktionelle Gruppen gegenübergestellt. Alle Formulierungen enthalten Fentanyl in einer Konzentration von 5 Gew.-%. Table 3 shows the results of permeation studies based on matrices a neutral Polyacrylatkfebers with free hydroxyl groups with and without such additives and a polyacrylate adhesive without other free functional Groups juxtaposed. All formulations contain fentanyl in one Concentration of 5% by weight.  

Tabelle 3 Table 3

Vergleichende Permeationsstudien mit Formulierungen mit und ohne löslichkeitsvermindernde Zusätze Comparative permeation studies with formulations with and without solubility-reducing additives

Formul. 2Formul. 2

5 Gew.-% Fentanyl in einem neutralen Polyacrylatkleber mit freien 5,2% Hydroxylgruppen5% by weight of fentanyl in a neutral polyacrylate adhesive with free 5.2% hydroxyl groups

Formul. 3Formul. 3

Fentanyl 5,0%
Polyacrylatkleber,
neutral mit freien 5,2% 55,0%
Hydroxylgruppen
Polypinen 15,0%
Glycerin 10,0%
Dioctylcyclohexan 15,0%Fentanyl 5.0%
polyacrylate,
neutral with free 5.2% 55.0%
hydroxyl
Polypins 15.0%
Glycerin 10.0%
Dioctylcyclohexane 15.0%

Formul. 4Formul. 4

5 Gew.-% Fentanyl in einem Polyacrylatkleber ohne freie funktionelle Gruppen5% by weight fentanyl in a polyacrylate adhesive without free functional groups

Die Ergebnisse der Permeationsstudie zeigen, daß die Permeationsrate durch den Zusatz von die Löslichkeit des Wirkstoffs in der Matrix reduzierenden Substanzen signifikant verbessert werden kann. In etwa die gleichen Ergebnisse erreicht man durch die Verwendung eines Klebers ohne freie funktionelle Gruppen, der auch ohne Zusätze über eine geringe Lösekapazität für den Wirkstoff verfügt. The results of the permeation study show that the permeation rate by the Addition of substances that reduce the solubility of the active ingredient in the matrix can be significantly improved. You get roughly the same results by using an adhesive without free functional groups, which too has a low dissolving capacity for the active ingredient without additives.  

Aus den Permeationsdaten lassen sich für verschiedene TTS-Stärken die jeweiligen TTS-Größen berechnen. Die Ergebnisse sind in Tabelle 4 gelistet.The permeation data can be used for different TTS strengths calculate the respective TTS sizes. The results are listed in Table 4.

Tabelle 4 Table 4

Aus Permeationsdaten errechnete TTS-Größen TTS sizes calculated from permeation data

Das Ergebnis der Berechnung zeigt, daß carboxylgruppenhaltige Kleber bei einer Fentanylkonzentration von 5% auch bei der niedrigsten Dosierung zu für den praktischen Gebrauch zu großen TTS führen. Bei den hydroxylgruppenhaltigen Klebern berechnen sich zwar auch recht große TTS, allerdings besteht hier durch die Erhöhung der Fentanylkonzentration die Möglichkeit, bei nicht zu hohen Konzentrationen, d. h. höchstens 20%, zu TTS mit einer für den praktischen Gebrauch geeigneten Größe zu kommen. Vereinfacht kann dabei angenommen werden, daß die thermodynamische Aktivität und damit auch die Permeationsraten linear von der Konzentration abhängen, solange der Wirkstoff vollständig gelöst vorliegt.The result of the calculation shows that carboxyl group-containing adhesives at one Fentanyl concentration of 5% even at the lowest dosage for the practical use lead to large TTS. For those containing hydroxyl groups Adhesives are also quite large TTS, but persist here increasing the fentanyl concentration the possibility of not being too high Concentrations, i.e. H. at most 20%, to TTS with one for the practical Use appropriate size to come. Simplified can be assumed be that the thermodynamic activity and thus the permeation rates linearly depend on the concentration, as long as the active ingredient is completely dissolved is present.

Durch Verwendung von die Löslichkeit senkenden Hilfsstoffen in Formulierungen mit hydroxylgruppenhaltigen Polyacrylatklebern bzw. durch die Verwendung von Polyacrylatklebern ohne freie funktionelle Gruppen erhält man schon bei einer Fentanylkonzentration von 5,0% TTS, die selbst in der höchsten Dosierung von 100 µg/h eine akzeptable Größe aufweisen. Natürlich bietet sich auch hier die Möglichkeit, durch eine Erhöhung der Fentanylkonzentration die Systemfläche weiter zu verkleinern. By using solubility-reducing auxiliaries in formulations with polyacrylate adhesives containing hydroxyl groups or by using One obtains polyacrylate adhesives without free functional groups Fentanyl concentration of 5.0% TTS, even in the highest dosage of 100 µg / h have an acceptable size. Of course, here too Possibility of increasing the system area by increasing the fentanyl concentration further downsize.  

Fentanyl und seine Derivate haben, wie schon eingangs erwähnt, einen engen therapeutischen Index. Dies bedeutet, daß zur Wirkung einerseits ein gewisser Schwellenwert, der bezüglich der Plasmakonzentration überschritten sein muß, andererseits bei höheren Konzentrationen schnell unakzeptable Nebenwirkungen auftreten. Es ist deshalb vorteilhaft, wenn das System zusätzlich eine Steuermembran enthält und damit den Wirkstofffluß durch die Haut unabhängig von der individuellen Hautbeschaffenheit auf einen Maximalwert begrenzt. Solche Membranen bestehen bevorzugt aus einem Copolymer aus Ethylen und Vinylacetat (EVA-Polymer) oder sind mikroporöse Folien auf der Basis von Polyethylen oder Polypropylen. Derartige Membranen gehören zum Stand der Technik. Im Falle der EVA-Polymere hängt die Wirkstoffdurchlässigkeit von dem Anteil des Vinylacetats und der Dicke der Membran ab. Gebräuchlich sind Membranen mit einem VA-Gehalt zwischen 2 und 25 Gewichtsprozenten und einer Dicke zwischen 25 und 100 µm, vorzugsweise zwischen 40 und 100 µm, wobei es bezüglich des Vinylacetat-Gehalts und der Dicke praktisch kaum Begrenzungen gibt. Für die jeweilige Formulierung müssen beide Parameter entsprechend gewählt werden, um die Begrenzung auf den gewünschten Maximalfluß aus dem TTS zu gewährleisten. Bei den mikroporösen Membranen erfolgt der Stofftransport nicht durch das Polymer, sondern lediglich durch die sich in diesen Membranen befindlichen Poren. Die Anzahl und Größe der Poren bestimmt dabei die maximale Abgaberate des TTS.As already mentioned, fentanyl and its derivatives have a narrow one therapeutic index. This means that on the one hand a certain Threshold that must be exceeded with regard to the plasma concentration, on the other hand, unacceptable side effects quickly occur at higher concentrations occur. It is therefore advantageous if the system also has a Control membrane contains and thus the active ingredient flow through the skin independently limited to a maximum by the individual skin condition. Such Membranes preferably consist of a copolymer of ethylene and Vinyl acetate (EVA polymer) or are microporous films based on Polyethylene or polypropylene. Such membranes are part of the prior art Technology. In the case of EVA polymers, the permeability to active ingredients depends on that Share of vinyl acetate and the thickness of the membrane. Are in use Membranes with a VA content between 2 and 25 percent by weight and a thickness between 25 and 100 µm, preferably between 40 and 100 µm, it is practically hardly in terms of vinyl acetate content and thickness Limitations there. Both parameters must be used for the respective formulation be chosen accordingly to limit the desired To ensure maximum flow from the TTS. With the microporous membranes the mass transfer does not take place through the polymer, but only through the itself pores in these membranes. The number and size of the pores determines the maximum delivery rate of the TTS.

Üblicherweise sind solche Membranen mit einem Kleberfilm zur Befestigung des TTS auf der Haut versehen. Besonders geeignet für Fentanyl und seine Derivate sind Kleberfilme auf Basis von selbstklebenden Polyacrylaten oder selbstklebenden Polysiloxanen. Der Vorteil von Polysiloxanen ist dabei, daß der Wirkstoff in diesen Polymerem sehr schlecht löslich ist und deshalb die Wirkstoffbeladung des TTS durch die Verwendung eines zusätzlichen Kleberfilms nicht unnötig gesteigert werden muß. Derartige Kleberfilme können jedoch auch bei Systemen angewendet werden, die keine Membranen, aber Matrixschichten mit geringerer Klebkraft enthalten. Such membranes are usually provided with an adhesive film for fastening the TTS on the skin. Particularly suitable for fentanyl and its derivatives are adhesive films based on self-adhesive polyacrylates or self-adhesive polysiloxanes. The advantage of polysiloxanes is that Active ingredient is very poorly soluble in these polymers and therefore the Active ingredient loading of the TTS through the use of an additional adhesive film need not be increased unnecessarily. However, such adhesive films can also be used in systems that do not have membranes but matrix layers included with less adhesive.  

Wie bei jedem TTS gibt es natürlich auch hier die Möglichkeit, die Barriereeigenschaften des menschlichen Stratum Corneum durch den Einsatz von permeationsfördernden Stoffen zu reduzieren. Solche Substanzen sind z. B. Fettsäuren, Fettalkohole, Fettsäureester, Ester des Glycerins mit mittel- bzw. langkettigen Fettsäuren und Glycole wie 1,2-Propandiol. Es können dabei alle Substanzen eingesetzt werden, die physiologisch unbedenklich und mit dem Wirkstoff und den anderen Hilfsstoffen verträglich sind.As with any TTS, there is of course also the option here Barrier properties of the human stratum corneum through the use of to reduce permeation-promoting substances. Such substances are e.g. B. Fatty acids, fatty alcohols, fatty acid esters, esters of glycerol with medium or long chain fatty acids and glycols such as 1,2-propanediol. Everyone can do it Substances are used that are physiologically safe and with the Active ingredient and the other excipients are compatible.

Zusammenfassend ist festzustellen, das Matrixsysteme im Sinne dieser Erfindung befriedigende bis gute Permeationsraten zeigen und auch die Herstellung von TTS mit einer akzeptablen Größe ermöglichen. Gleichzeitig ist eine Gefährdung des Patienten durch eine zu hohe Wirkstoffaufnahme infolge einer Undichtigkeit unmöglich. Insgesamt stellen damit Matrixsysteme auf Basis von Polyacrylatklebern im Sinne dieser Erfindung für Fentanyl und seine Analogen bezüglich der Patientensicherheit einen bedeutenden Fortschritt gegenüber dem bekannten Stand der Technik dar.In summary it can be stated that matrix systems in the sense of this invention show satisfactory to good permeation rates and also the production of Enable TTS with an acceptable size. At the same time is a hazard of the patient due to excessive drug intake due to a leak impossible. Overall, matrix systems based on Polyacrylate adhesives for the purposes of this invention for fentanyl and its analogs a significant advance over patient safety in terms of patient safety known prior art.

BeispieleExamples Beispiel 1 (Formulierung 1, 2, 4)Example 1 (formulation 1, 2, 4)

Fentanyl (freie Base) wird in der Lösung des Klebers im Heptan/Ethylacetat gelöst. Die Menge an Fentanyl wird dabei so berechnet, daß sich, bezogen auf den Feststoffgehalt der Kleberlösung, eine Konzentration von 5,0 Gew.-% ergibt. Die resultierende Masse wird mit einem Rakel auf eine silikonisierte Polyesterfolie vor Gebrauch zu entfernende Schutzschicht, in einer Dicke beschichtet, daß sich nach dem Entfernen der Lösemittel ein Gewicht der Beschichtung von ca. 80 g/m2 ergibt. Nach dem Entfernen der Lösemittel wird der getrocknete Film mit einer dünnen Polyesterfolie (Rückschicht des TTS) kaschiert, und aus dem Gesamtlaminat werden die fertigen TTS ausgestanzt.Fentanyl (free base) is dissolved in the solution of the adhesive in heptane / ethyl acetate. The amount of fentanyl is calculated so that, based on the solids content of the adhesive solution, there is a concentration of 5.0% by weight. The resulting mass is coated with a doctor knife onto a siliconized polyester film protective layer to be removed before use in a thickness such that the weight of the coating after removal of the solvent is approximately 80 g / m 2 . After removing the solvents, the dried film is laminated with a thin polyester film (back layer of the TTS), and the finished TTS are punched out from the total laminate.

Beispiel 2 (Formulierung 3)Example 2 (formulation 3)

5,0 g Fentanyl, 15,0 g Polypinen, 10,0 g Glycerin, 15,0 g Dioctylcyclohexan und 110 g der Kleberlösung mit einem Feststoffgehalt von 50,0 Gew.-% werden zusammengegeben und bis zum Auflösen des Fentanyls gerührt.5.0 g fentanyl, 15.0 g polypins, 10.0 g glycerol, 15.0 g dioctylcyclohexane and 110 g of the adhesive solution with a solids content of 50.0 wt .-% added together and stirred until the fentanyl dissolves.

Die resultierende Masse wird mit einem Rakel auf eine silikonisierte Polyesterfolie (vor Gebrauch zu entfernende Schutzschicht) in einer Dicke beschichtet, daß sich nach dem Entfernen der Lösemittel ein Gewicht der Beschichtung von ca. 80 g/m2 ergibt. Nach dem Entfernen der Lösemittel wird der getrocknete Film mit einer dünnen Polyesterfolie (Rückschicht des TTS) kaschiert und aus dem Gesamtlaminat werden die fertigen TTS ausgestanzt.The resulting mass is coated with a doctor blade onto a siliconized polyester film (protective layer to be removed before use) in a thickness such that the weight of the coating after removal of the solvent is approximately 80 g / m 2 . After removing the solvent, the dried film is laminated with a thin polyester film (backing of the TTS) and the finished TTS are punched out of the total laminate.

Claims (11)

1. Transdermales Therapeutisches System (TTS) bestehend aus einer wirkstoffundurchlässigen Rückschicht, zumindest einer Fentanyl oder einen fentanylanalogen Wirkstoff enthaltenden Matrixschicht auf Basis von Polyacrylat und einer vor Gebrauch zu entfernenden Schutzschicht, dadurch gekennzeichnet, daß das Polyacrylat selbstklebend und frei von Carboxylgruppen ist, für Fentanyl eine Sättigungslöslichkeit zwischen 3 und 20 Gewichtsprozenten aufweist, und daß die wirkstoffhaltigen Schichten mindestens 80 Gewichtsprozent des eingearbeiteten Wirkstoffs in molekulardispers gelöster Form enthalten.1. Transdermal therapeutic system (TTS) consisting of an active substance-impermeable backing layer, at least one fentanyl or a fentanylan-analog active substance-containing matrix layer based on polyacrylate and a protective layer to be removed before use, characterized in that the polyacrylate is self-adhesive and free of carboxyl groups for fentanyl has a saturation solubility between 3 and 20 percent by weight and that the active ingredient-containing layers contain at least 80 percent by weight of the incorporated active ingredient in a molecularly dispersed form. 2. TTS gemäß Anspruch 1, dadurch gekennzeichnet, daß das Polyacrylat für Fen­ tanyl eine Sättigungslöslichkeit zwischen 4 und 12 Gewichtsprozenten aufweist.2. TTS according to claim 1, characterized in that the polyacrylate for fen tanyl has a saturation solubility between 4 and 12 percent by weight. 3. TTS gemäß Anspruch 1, dadurch gekennzeichnet, daß das Polyacrylat für Fen­ tanyl eine Sättigungslöslichkeit zwischen 5 und 10 Gewichtsprozenten aufweist.3. TTS according to claim 1, characterized in that the polyacrylate for fen tanyl has a saturation solubility between 5 and 10 percent by weight. 4. TTS gemäß Anspruch 1, dadurch gekennzeichnet, daß das Polyacrylatpolymer über keine freien funktionellen Gruppen verfügt und lediglich aus Monomeren und/ oder der Acryl-Methacrylsäureester und gegebenenfalls zusätzlich aus anderen polymerisierbaren Vinylverbindungen ohne freie funktionelle Gruppen in Mengen von bis zu 50 Gew.-%, insbesondere Vinylacetat aufgebaut ist.4. TTS according to claim 1, characterized in that the polyacrylate polymer has no free functional groups and only from monomers and / or the acrylic methacrylic acid ester and optionally additionally other polymerizable vinyl compounds without free functional groups is built up in amounts of up to 50% by weight, in particular vinyl acetate. 5. TTS gemäß Anspruch 1, dadurch gekennzeichnet, daß das dem Polyacrylat zugrunde liegende Monomerengemisch bis zu 20 Gew.-% Monomere mit freien funktionellen Gruppen in Form von 2-Hydroxyethylacrylat und/oder - methacrylat enthält.5. TTS according to claim 1, characterized in that the polyacrylate underlying monomer mixture with up to 20% by weight of monomers free functional groups in the form of 2-hydroxyethyl acrylate and / or - contains methacrylate. 6. TTS gemäß einem oder mehreren der Ansprüche 1-5, dadurch gekennzeichnet, daß es als weitere Schicht zusätzlich eine Steuermembran enthält. 6. TTS according to one or more of claims 1-5, characterized in that that it also contains a control membrane as a further layer.   7. TTS gemäß Anspruch 6 dadurch gekennzeichnet, daß es zusätzlich eine sich hautwärts auf der Membran befindende selbstklebende Schicht zur Befestigung auf der Haut enthält.7. TTS according to claim 6, characterized in that it is additionally a Self-adhesive layer on the membrane for attachment to the skin contains on the skin. 8. TTS gemäß Anspruch 6 oder 7, dadurch gekennzeichnet, daß die Steuermembran aus einem Ethylen-Vinylacetat-Copolymer, zweckmäßig mit einem Vinylacetatanteil von bis zu 25 Gew.-%, oder einer mikroporösen Folie auf Basis von Polyethylen oder Polypropylen besteht und zweckmäßig eine Dicke zwischen 25 und 100, vorzugsweise zwischen 40 und 100 µm aufweist.8. TTS according to claim 6 or 7, characterized in that the Control membrane made of an ethylene-vinyl acetate copolymer, advantageously with a Vinyl acetate content of up to 25% by weight, or a microporous film based of polyethylene or polypropylene and suitably a thickness between 25 and 100, preferably between 40 and 100 microns. 9. TTS gemäß einem oder mehreren der Ansprüche 1-8, dadurch gekennzeichnet, daß die wirkstoffhaltigen Schichten zusätzlich die Permeationsrate durch menschliche Haut verbessernde Substanzen enthalten, insbesondere Glykole und/ oder solche, die zur Gruppe der Fettsäure, Fettsäureester, Fettalkohole oder Glycerinester gehören.9. TTS according to one or more of claims 1-8, characterized in that the active ingredient-containing layers additionally through the permeation rate contain human skin-improving substances, in particular glycols and / or those belonging to the group of fatty acids, fatty acid esters, fatty alcohols or Include glycerol esters. 10. TTS gemäß einem oder mehreren der Ansprüche 1-9, dadurch gekennzeichnet, daß die wirkstoffhaltigen Schichten Substanzen enthalten, die die Löslichkeit des Wirkstoffs in diesen Schichten erniedrigen.10. TTS according to one or more of claims 1-9, characterized in that the active ingredient-containing layers contain substances that increase the solubility of the Lower active ingredient in these layers. 11. TTS gemäß Anspruch 10, dadurch gekennzeichnet, daß die die Löslichkeit erniedrigenden Substanzen bei Raumtemperatur flüssige Kohlenwasserstoffe, insbesondere Dioctylcyclohexan oder flüssiges Paraffin, Kohlenwasserstoffharze, insbesondere Polypinenharze oder Polyethylenglykol oder Glycerin sind.11. TTS according to claim 10, characterized in that the solubility degrading substances liquid hydrocarbons at room temperature, in particular dioctylcyclohexane or liquid paraffin, hydrocarbon resins, are in particular polypine resins or polyethylene glycol or glycerin.
DE10141650A 2001-08-24 2001-08-24 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate Ceased DE10141650C1 (en)

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DE10141650A DE10141650C1 (en) 2001-08-24 2001-08-24 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
JP2003522590A JP5405709B2 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system containing fentanyl or related substances
EP02762336A EP1418894B1 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl
KR1020047002655A KR100895189B1 (en) 2001-08-24 2002-07-10 Transdermal Therapy System Containing Fentanyl or Fentanyl-Like Substances
ES02762336T ES2280563T3 (en) 2001-08-24 2002-07-10 TRANSDERMAL THERAPEUTIC SYSTEM WITH FENTANIL.
PCT/EP2002/007664 WO2003018075A2 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl or related substances
CNA028164261A CN1713899A (en) 2001-08-24 2002-07-10 Transdermal therapeutic systems containing fentanyl or its related substances
AU2002328328A AU2002328328B2 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl or related substances
MXPA04001676A MXPA04001676A (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl or related substances.
CN2011101937323A CN102258501A (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl or related substances
DE20221160U DE20221160U1 (en) 2001-08-24 2002-07-10 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
BR0212026-7A BR0212026A (en) 2001-08-24 2002-07-10 Fentanyl or similar transdermal therapeutic system
DE20221087U DE20221087U1 (en) 2001-08-24 2002-07-10 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
PT02762336T PT1418894E (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl
DE50209364T DE50209364D1 (en) 2001-08-24 2002-07-10 Transdermales therapeutisches system mit fentanyl
EP07001087A EP1825849A1 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system comprising fentanyl
EP07001088A EP1782799A3 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system comprising an active analogue of fentanyl
DE20221161U DE20221161U1 (en) 2001-08-24 2002-07-10 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
US10/487,393 US10568845B2 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl or related substances
CA2457401A CA2457401C (en) 2001-08-24 2002-07-10 Transdermal therapeutic system containing fentanyl or related substances
DK02762336T DK1418894T3 (en) 2001-08-24 2002-07-10 Transdermal therapeutic system with fentanyl
DE20221159U DE20221159U1 (en) 2001-08-24 2002-07-10 Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
AT02762336T ATE352293T1 (en) 2001-08-24 2002-07-10 TRANSDERMAL THERAPEUTIC SYSTEM WITH FENTANYL
ZA200400314A ZA200400314B (en) 2001-08-24 2004-01-15 Transdermal therapeutic system with fentanyl or related substances.
CY20071100407T CY1106411T1 (en) 2001-08-24 2007-03-22 INTERMEDIATE THERAPEUTIC SYSTEM WITH FENTANYL
JP2010232409A JP5639843B2 (en) 2001-08-24 2010-10-15 Transdermal therapeutic system containing fentanyl or related substances
US16/263,743 US10583093B2 (en) 2001-08-24 2019-01-31 Transdermal therapeutic system with fentanyl or related substances
US16/719,086 US10940122B2 (en) 2001-08-24 2019-12-18 Transdermal therapeutic system with fentanyl or related substances

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